Immunomodulators are substances that modulate the immune system by suppressing or stimulating an immune response. They work through various mechanisms including antigen recognition, phagocytosis, lymphocyte proliferation, antibody synthesis, and release of immune mediators. Clinically used immunomodulators can be categorized as immunostimulants or immunosuppressants. Immunostimulants enhance immune function and include substances like levamisole, thalidomide, BCG vaccine, interferons, and interleukin-2. Immunosuppressants suppress immune function and are used for organ transplantation, autoimmune diseases, and graft-versus-host disease prevention following stem cell transplant. Common immunosuppressants include glucocorticoids

1. Immunomodulators :-Mode and Mechanism Of Their Action
Subject :- Pharmaceutical Biotechnology
DEPARTMENT OF PHARMACEUTICAL SCIENCES
Dr. HARISINGH GOUR VISHWAVIDYALAYA
Sagar ( M.P)- 470003, India
(A Central University )
SUBMITTED BY :-
SUMIT S. KOLTE
( M Pharm Sem I )
Pharmaceutics
SUBMITTED TO :-
Prof. UMESH K PATIL
(Professor, DOPS)
DR. UDITAAGARWAL
(Guest Faculty, DOPS)
Ms. POOJA DAS BIDLA
(Research Scholar, DOPS)
Session 2023-2024

2. CONTENTS
 Introduction
 Components of immune system
 Types Of Immunity
 Mechanism of Immunomodulators
 Clinically Used Immunomodulators
 Immunomodulators Types
 References

3. INTRODUCTION
 Immunity :-is the ability of the body to protect against all types of foreign bodies
like bacteria ,virus ,toxic substances etc. Which enter the body or resistance
acquired by a host towards injury caused by microorganisms and their products.
 As it protects us from diseases it is also called disease resistance
 Everyday our body comes in contact with several pathogens ,but only a few
results into diseases.
 The reasons is our body has the ability to release antibodies against these
pathogens and protects the body against diseases.
 These defence mechanism is called as immunity / immune system
 Substances capable of stimulating immune mechanism are called as antigens.

4. COMPONENTS OF THE IMMUNE SYSTEM
Lymphocytes, Cellular Immunity, Humoral, Immunoglobulin, Lymph Nodes, Spleen , Thymus

5. TYPES OF IMMUNITY
There are two types of immunity :- 1) Active immunity 2) Passive immunity
Antibodies developed in response to.. Antibodies received from….

6. MECHANISM OF IMMUNOMODULATOR
Immunomodulator :- Immunomodulator are the agents that modulates the immune system
by supress or stimulate the immune response .
There are one or more following steps :-
 Antigen recognition
 phagocytosis
 Lymphocyte proliferation
 Synthesis of antibodies
 Release of mediators due to immune response
 Modification of target tissue response

7. ANTIGEN RECOGNITION
 Antigen recognition by T cells is a sophisticated process mediated by the T cell
receptor (TCR).
 Two key features distinguish T cell antigen recognition from most surface receptors
that are pre-committed to recognition of a specific ligand.
 First, the antigen-binding region of the TCR is generated by a process that involves
modification of DNA at the TCR locus with random addition and deletion of
nucleotides. This results in an immense diversity in the antigen-binding regions of
the TCR chains.
 Second, the receptor represents a very sensitive antigen recognition receptor.

8. PHAGOCYTOSIS
 Phagocytosis is a cellular process for ingesting and eliminating particles larger than
0.5 um in diameter, including microorganisms, foreign substances, and apoptotic
cells.
 only specialized cells termed professional phagocytes accomplish phagocytosis with
high efficiency.
 Macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts are among
these dedicated cells.
 These professional phagocytes express several phagocytic receptors that activate
signaling pathways resulting in phagocytosis.
 The process of phagocytosis involves several phases: i) detection of the particle to
be ingested, ii) activation of the internalization process, ii) formation of a specialized
vacuole called phagosome, and iv) maturation of the phagosome to transform it into
a phagolysosome.

9. LYMPHOCYTE PROLIFERATION
 Lymphocyte proliferation is the main step in a proper immune response to create
effector lymphocytes,
 necessary to eliminate a current antigen, or memory lymphocytes,
 necessary to eliminate the same antigen the host may encounter in the future; this
memory function insures that future responses to an antigen are faster and stronger
compared to the first encounter.
 T lymphocytes, including the helper (th) cells, which help other white blood cells in
the immune response, and cytotoxic t lymphocytes, which destroy virus-infected
cells and tumor cells, help a proper cell-mediated immune response.
 B lymphocytes, including antibody-producing plasma cells, help a proper humoral
immune response.

10. SYNTHESIS OF ANTIBODIES
 Antibodies are produced by specialized white blood cells called B lymphocytes (or B
cells).
 When an antigen Binds to the B-cell surface, it stimulates the B cell to divide and mature
into a group of identical cells called a clone.
 The mature B cells, called plasma cells, secrete millions of antibodies into the
bloodstream and lymphatic system.
 How do antibodies work

11. • The importance of immune system in protecting the body against harmful molecules is well
recognized.
However, in some instances, this protection can result in serious problems.
e.g. the introduction of allograft can elicit a damaging immune response causing rejection of
the transplanted tissue.
Because the person's immune system detects that the antigens on the cells of the organ are
different or not "matched.“
• The ability of recipient t cells to recognize donor-derived antigens, called allorecognition,
initiates allograft rejection
• Benefits of immunomodulators stem from their ability to stimulate natural & adaptive
defence mechanisms, such as cytokines, which enables the body to help itself.
• Natural immunomodulators act to strengthen weak immune systems & to moderate immune
systems that are overactive
• Plant sterols & sterolins are natural immunomodulators found in some raw fruits &
vegetables & in the alga, spirulina

12. CLINICALLY USED IMMUNOMODULATORS

13. IMMUNOMODULATOR TYPES
All drugs which modify immune response generally categorized as immunomodulators.
These can either function as:
1. Immunostimulants 2. Immunosuppressants

14. IMMUNOSTIMULANTS
 Immunostimulant, also known as immunostimulators are substances (drugs and
nutrients) that stimulate the immune system by inducing activation or increasing
activity of any of its components.
 It includes :- levamisole , thalidomide , BCG , recombinant cytokines- interferons,
interferon alfa-2b, interleukin-2
1) Levamisole
• Levamisole is orally active levo isomer of tetramisole, restores depressed t-cell
function.
• Used as an adjunct in malignancies, aphthous ulcers and recurrent herpes, also used
as disease modifying drug in rheumatoid arthritis.
• Leads to decrease in metabolic inactivation of c-GMP accompanie with increased
breakdown of c-AMP.

15. 2)Thalidomide
• Thalidomide works on the immune system to reduce inflammation
• It also interferes with the growth of multiple myeloma cells, which are eventually
destroyed in the body.
• Thalidomide is an antineoplastic (cancer medicine) and lepro static agent.
3) Bacillus Calmate Guerin (BCG) Vaccine:
 It is used as immunological enhancer to stimulate intact immune system (i.e. a non
specific immune enhancer ) of the body.
 It causes stimulation of macrophage function, phagocytic activity, lysosomal
enzyme activity and chemotaxis mechanisms.
 It induces the production of lymphocyte-activity factor resulting of phase I of
immune response.
 Because of its activity against tumor antigen, it is beneficial in treatment of lung &
breast cancer, acute lympholytic & myelogenous leukemia.
• BCG & its methanol extracted residue (MER) contain muramyl dipeptide as an
active immunostimulant ingredient.
• T-lymphocytes are principle target cells for the action of BCG vaccine

16. 4) Interferons
 A natural substance that helps the body's immune system fight infection and other diseases, such as
cancer.
 Low molecular weight glycoprotein cytokines produced by host cells in response to viral infections
 Bind to cell surface receptors - initiate intracellular event :
- enzyme induction
-Inhibition of cell proliferation
-Affect viral replication
-Increased phagocytosis
 Immunomodulatory activity
5) Interferon Alfa-2b
 It binds to and activates human type 1 interferon receptors causing them to dimerize & this
activates the JAK/STAT pathway.
 Activation of the JAK/STAT pathway increases expression of multiple genes in multiple tissues
involved in the innate antiviral response.
6) Interleukin-2
 Interleukin-2 is made by a type of T lymphocyte.
 It increases the growth and activity of other t lymphocytes and b lymphocytes and affects the
development of the immune system.

17. IMMUNOSUPPRESSANTS
• Immunosuppressant are a class of drugs that suppress, or reduce, the strength of the
body's immune system.
• The body's immune system helps fight off infections that cause illness.
• But sometimes, the immune system mistakenly attacks healthy cells and tissues.
• Immunosuppressants can slow or stop the response.
• Immunosuppressants have their major use/role in organ transplantation &
autoimmune disease & Stem cell / bone marrow transplant.

18.  Autoimmune disease :
- A condition in which the body's immune system mistakes its own healthy tissues as
foreign and attacks them.
- Depending on which part of the body is under attack, this response can lead to
different types of autoimmune diseases.
- Immunosuppressants hold back the immune system, helping to prevent cell damage
and inflammation & These drugs minimize Symptoms.
- These autoimmune diseases are :-
• Alopecia areata
• Inflammatory bowel disease
• Lupus
• Psoriasis

19.  Organ transplant
- people who get organ transplants, immunosuppressants help prevent organ rejection.
- Our immune system knows the new organ isn't part of our original body.
- It perceives the new organ as a threat and will try to destroy it.
- Immunosuppressants control this response, protecting the new organ.
 Stem cell/ bone marrow transplant
- Allogeneic stem cell transplants replace diseased cells in our body with healthy ones
from a donor (called graft).
- After a transplant, donor cells begin to build a new immune system in our body (the
host).
- Sometimes, this new immune system views our body as foreign. The immune
system may attack healthy tissues and organs. This leads to graft-versus-host disease
(GVHD).
- Immunosuppressants lower the chances of GVHD

20. LIST OF SOME IMMUNOSUPPRESSANTS:
 Glucocorticoids
- Induce redistribution of lymphocytes decrease in peripheral blood lymphocyte counts.
- Down regulation of IL-1, IL-2, IL-3, IL-6.
- Inhibition of T cell proliferation
- Increase number of RBCs, platelets & neutrophils in circulation
- Enhance rate of destruction of lymphoid cells.
 Uses: Transplant rejection
• GVH (graft-versus-host ) –Bone Marrow transplantation
• Autoimmune diseases- Rheumatoid arthritis, Systemic lupus erythematosus,
Haematological conditions
• For Psoriasis
• Inflammatory Bowel Disease & Eye conditions
 Adverse effect :- Growth retardation , Avascular Necrosis of Bone , Risk of Infection ,
Poor wound healing , Cataract , Hyperglycemia ,Hypertension

21.  Calcineurin inhibitors
- It includes cyclosporine and Tacrolimus
- Most effective immunosuppressive drugs
- Target intracellular signaling pathway
- Blocks induction of cytokines genes
1. Cyclosporine :-
• Extracted from a soil fungus
• Selectively inhibits T lymphocytes proliferation and other cytokine production and
response of inducer T cells to IL-1 ,without any effect on suppressor T cells
• Binds to the cytosolic protein cyclophilin(immunophilin) of immunocompetent
lymphocytes, especially T-lymphocyte
• This complex of cyclosporine & cyclophilin inhibit calcineurin, which under normal
circumstances, is responsible for activating the transcription of IL-2
• It also inhibits lymphokine production & IL release, leads to a reduced function of
effector T-cells, does not affect cytostatic activity.

22. Uses :-
- Prevent rejection of kidney, liver, cardiac, Bone Marrow & other allogeneic transplants
- More effective when glucocorticoids are also administered
- Useful in autoimmune disease
- For induction it is started orally 12 Hours before the transplant & continued for as long
as needed.
Adverse effect :- Hypertension , Hyperlipidemia , Gum hyperplasia , Hyperuricemia -
worsens gout , Calcineurin inhibitors + Glucocorticoids=Diabetogenic , Renal dysfunction
2. Tacrolimus
• Chemically different from cyclosporine, newer immunosuppressant
• Macrolide that is isolated from soil fungus
• Binds to different cytoplasmic immunophilin protein labelled FK506 binding protein
(FKBP)
• Give Orally as well as i.v infusion
• Metabolized by CYP3A4 & excreted in bile & plasma t/ is 12hrs
• 100 times more potent than cyclosporine

23. Adverse effect :-
 Nephrotoxicity
 Neurotoxicity- Tremor, headache, motor disturbances, seizures GI complaints
 Hypertension
 Hyperglycaemia
 Antiproliferative and Antimetabolic drugs: includes-
o M-TOR (mammalian target of rapamycin) inhibitors : Sirolimus , Everolimus
o Azathioprine (purine antimetabolite ) –uses in RA
o Mycophenolate mofetil – prodrug of mycophenolic acid ,inhibits inosine
monophosphate dehydrogenase –enzyme in guanine synthesis
o Cyclophosphamide –in RA
o Methotrexate (folate antagonist )
o Chlorambucil
o Thalidomide

25. REFERENCES
 Essentials Of Medical Pharmacology: K.D. Tripathi. 7th Edition
 Autran B, Carcelain G, Combadiere B, Debre P. Thero. 305(5681) Vaccines For
Chronic Infections. Science 2004: 305 (5681) :205-208
 Michie HR, Managuen KR, Spriggs DR. Detection Of Circulating Tumor Necrosis
Factor After Endotoxin Administartion. N Engl J Med. 1988;318:1481-148
 Borden EC. Interferons-expanding Therapeutic Role. N Engl J Med.
1992;326:1491-1493
 Patil U.S, Jaydeokar A.V, Bandawane D.D, Immunomodulators: A Pharmacological
Review, International Journal Of Pharmacy & Pharmaceutical Sciences, Vol
4, Suppl 1, 2012